Angewandte
Chemie
DOI: 10.1002/anie.201202092
Allylic Thioethers
Enantioselective Allylic Thioetherification: The Effect of Phosphoric
Acid Diester on Iridium-Catalyzed Enantioconvergent
Transformations**
Markus Roggen and Erick M. Carreira*
Iridium-catalyzed allylic substitution reactions have estab-
lished themselves as useful, viable processes for the produc-
tion of valuable building blocks.[1] The collection of nucleo-
philes used in this transformation has been expanded
dramatically in recent years[2] to include amines,[3] alkoxides
and bicarbonates,[4] silyl enol ethers,and malonate diesters.[5]
The direct use of a heteroatom nucleophile without prior
activation by conversion into a salt has been reported for only
a few cases, such as ammonia,[6] alcohols, and phenols.[7]
Iridium-catalyzed enantioselective allylations of sulfur nucle-
ophiles[8] are also known, involving thiophenolates,[9] aliphatic
unsymmetrical ethers.[17] In seeking to further expand the
scope and use of allylic alcohols, we have examined the use of
thiols directly.[18]
The primary challenge in using racemic electrophiles in
enantioselective allylation is the inherent rate difference of
the two enantiomers. A variety of approaches to overcome or
exploit this rate difference have been developed, such as
dynamic kinetic resolution (DKR), dynamic kinetic asym-
metric transformation (DYKAT), and parallel kinetic reso-
lution (PKR).[19] A notable example of the latter is the report
by Hartwig and co-workers in which the kinetic resolution of
racemic branched allylic benzoates leads to substitution
products in 37–48% yield based on the allylic substrate,
while the other enantiomer is converted to the linear allylic
benzoate.[20] A lesser known approach is termed direct
enantioconvergent transformation (DET). In this process
the substrate enantiomers react by two distinctly different
mechanistic pathways to give the same product enantiomer.
The criteria for DET are rather difficult to meet, and
consequently this transformation has been scarcely
reported.[21]
thiolates,[10]
sodium
sulfide,[11]
sulfinates,[12]
and
iPr3SiSNa.[13,14] Herein, we report the direct, enantioselective
thioetherification of branched racemic allylic alcohols with
thiols to form optically active, secondary allylic thioethers
(Scheme 1). We also document our mechanistic findings,
Our investigations into the enantioselective allylic thio-
etherification commenced with conditions involving the
reaction of allylic alcohol 1a with 1.2 equiv of BnSH,
0.5 equiv of 3-chlorobenzoic acid as a Brønsted acid promoter
and [{Ir(cod)Cl}2] with ligand 3 in Cl(CH2)2Cl (DCE) at 508C.
Complete consumption of 1a was observed and 2a was
isolated with an e.r. of 86.5:13.5 [Eq. (1)]. In contrast to prior
observations with this catalyst in which formation of only the
branched product was noted, a 3:2 mixture of thioether
products 2a and 4a was observed.[22]
Scheme 1. Direct, enantioconvergent substitution of branched allylic
alcohols with thiols.
which implicate a rare example of a direct enantioconvergent
transformation (DET), which renders the formation of allylic
sulfides from allylic alcohols highly efficient.
We have previously reported the iridium-catalyzed allylic
substitution of branched allylic alcohols with sulfamic acid, as
an ammonia surrogate, in both enantiospecific[15] and enan-
tioselective[16] syntheses of allylic amines. The approach has
been expanded to include alcohols as nucleophiles to provide
The observation of 4a and the difficulty in improving the
selectivity, despite extensive experimentation, led to a study
of the mechanism.[23] Our previous work on allylic ether-
ification reactions demonstrated that a Brønsted acid is
required to promote alcohol activation and substitution.[17]
However, we noted that in the absence of acid catalyst thiols
participate in the substitution reaction, albeit conversions
above 60% were not observed. The first important mecha-
[*] M. Roggen, Prof. Dr. E. M. Carreira
ETH Zꢀrich, HCI H335
8093 Zꢀrich (Switzerland)
E-mail: carreira@org.chem.ethz
[**] M.R. acknowledges the Stipendienfonds Schweizerische Chemische
Industrie (SSCI) and the Swiss National Science Foundation.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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